The Wiskott-Aldrich syndrome
2006; Elsevier BV; Volume: 117; Issue: 4 Linguagem: Inglês
10.1016/j.jaci.2006.02.005
ISSN1097-6825
Autores Tópico(s)Blood disorders and treatments
ResumoThe Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with variable clinical phenotypes that correlate with the type of mutations in the WAS protein (WASP) gene. WASP, a key regulator of actin polymerization in hematopoietic cells, has 5 well-defined domains that are involved in signaling, cell locomotion, and immune synapse formation. WASP facilitates the nuclear translocation of nuclear factor κB and was shown to play an important role in lymphoid development and in the maturation and function of myeloid monocytic cells. Mutations of WASP are located throughout the gene and either inhibit or dysregulate normal WASP function. Analysis of a large patient population demonstrates a phenotype-genotype correlation: classic WAS occurs when WASP is absent, X-linked thrombocytopenia when mutated WASP is expressed, and X-linked neutropenia when missense mutations occur in the Cdc42-binding site. The progress made in dissecting the function of WASP has provided new diagnostic possibilities and has propelled our therapeutic strategies from conservative symptomatic treatment to curative hematopoietic stem cell transplantation and toward gene therapy. The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with variable clinical phenotypes that correlate with the type of mutations in the WAS protein (WASP) gene. WASP, a key regulator of actin polymerization in hematopoietic cells, has 5 well-defined domains that are involved in signaling, cell locomotion, and immune synapse formation. WASP facilitates the nuclear translocation of nuclear factor κB and was shown to play an important role in lymphoid development and in the maturation and function of myeloid monocytic cells. Mutations of WASP are located throughout the gene and either inhibit or dysregulate normal WASP function. Analysis of a large patient population demonstrates a phenotype-genotype correlation: classic WAS occurs when WASP is absent, X-linked thrombocytopenia when mutated WASP is expressed, and X-linked neutropenia when missense mutations occur in the Cdc42-binding site. The progress made in dissecting the function of WASP has provided new diagnostic possibilities and has propelled our therapeutic strategies from conservative symptomatic treatment to curative hematopoietic stem cell transplantation and toward gene therapy. The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disease with a characteristic clinical phenotype that includes thrombocytopenia with small platelets, eczema, recurrent infections caused by immunodeficiency, and an increased incidence of autoimmune manifestations and malignancies.1Wiskott A. Familiärer, angeborener Morbus Werlhofii?.Monatsschr Kinderheilkd. 1937; 68: 212-216Google Scholar, 2Aldrich R.A. Steinberg A.G. Campbell D.C. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea.Pediatrics. 1954; 13: 133-139PubMed Google Scholar, 3Sullivan K.E. Mullen C.A. Blaese R.M. Winkelstein J.A. A multiinstitutional survey of the Wiskott-Aldrich syndrome.J Pediatr. 1994; 125: 876-885Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar The identification of the molecular defect in 19944Derry J.M. Ochs H.D. Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome.Cell. 1994; 78: 635-644Abstract Full Text PDF PubMed Scopus (570) Google Scholar has broadened the clinical spectrum of the syndrome to include chronic or intermittent X-linked thrombocytopenia (XLT), a relatively mild form of WAS,5Villa A. Notarangelo L. Macchi P. Mantuano E. Cavagni G. Brugnoni D. et al.X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene.Nat Genet. 1995; 9: 414-417Crossref PubMed Google Scholar, 6Notarangelo L.D. Mazza C. Giliani S. D'Aria C. Gandellini F. Ravelli C. et al.Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia.Blood. 2002; 99: 2268-2269Crossref PubMed Scopus (50) Google Scholar and X-lined neutropenia caused by an arrest of myelopoiesis.7Devriendt K. Kim A.S. Mathijs G. Frints S.G. Schwartz M. Van Den Oord J.J. et al.Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.Nat Genet. 2001; 27: 313-317Crossref PubMed Scopus (207) Google Scholar In this review we will describe the clinical presentations associated with mutations of the WAS protein (WASP) gene, the laboratory abnormalities, the known functions of WASP, and evidence for a strong genotype-phenotype correlation. The incidence of the classic WAS phenotype has been estimated to be between 1 and 10 in 1 million individuals.8Ryser O. Morell A. Hitzig W.H. Primary immunodeficiencies in Switzerland: first report of the national registry in adults and children.J Clin Immunol. 1988; 8: 479-485Crossref PubMed Google Scholar, 9Stray-Pedersen A. Abrahamsen T.G. Froland S.S. Primary immunodeficiency diseases in Norway.J Clin Immunol. 2000; 20: 477-485Crossref PubMed Scopus (74) Google Scholar With broader awareness of the different clinical phenotypes, along with the availability of reliable diagnostic tools, the incidence might be much higher. Clinical manifestations suggesting WAS-XLT are often present at birth and consist of petechiae, bruising, and bloody diarrhea.1Wiskott A. Familiärer, angeborener Morbus Werlhofii?.Monatsschr Kinderheilkd. 1937; 68: 212-216Google Scholar Excessive hemorrhage after circumcision is an early diagnostic sign. Eczema is a frequent manifestation of classic WAS during infancy and childhood. The most consistent finding at diagnosis of both classic WAS and XLT is thrombocytopenia and small platelets. Infections, including otitis media with drainage of mucoid purulent material, pneumonia most often caused by bacteria and rarely by Pneumocystis carinii, and skin infections, are frequent complaints during the first 6 months of life. Patients with XLT have less problems with eczema and infections and often receive misdiagnoses of idiopathic thrombocytopenia (ITP), considerably increasing the actual age of diagnosis. X-linked neutropenia caused by missense mutations in the Cdc42-binding domain does not resemble classic WAS or XLT. To delineate these strikingly different clinical phenotypes (Table I), we have generated a simple scoring system.10Ochs H.D. The Wiskott-Aldrich syndrome.Isr Med Assoc J. 2002; 4: 379-384PubMed Google ScholarTable IClinical phenotypes associated with mutations of the WASP geneWASXLTIXLTXLNPhenotype Thrombocytopenia++(+)− Small platelets+++− Eczema+/++/+++−/+−− Immune deficiency+/++−/(+)−− Infections+/++−/(+)−+∗Infections typical for neutropenia. Autoimmunity and/or malignanciesFrequentPossible−− Congenital neutropenia−−−+ Disease scores3, 4, or 51, 2, or (5)†Patients with XLT with a score of 1 or 2 might progress to a score of 5. Incidence of autoimmunity and malignancies are less in XLT than in WAS.<10 WASP mutationsNonsense; frame shift caused by deletions, insertions; splicing defectsMissense (exons 1-3); inframe deletions or insertionsMissenseMissense in Cdc42-binding site WASP expressionAbsent or truncatedPresent, reduced quantityPresent, normal quantitiyPresentTreatment IVIGYesNo (with exceptions)NoNo HSCTYes at an early ageMight be considered if there is a sibling donorNo? SplenectomyNoMight be considered‡Splenectomy results in increased platelet numbers and reduced bleeding but causes a marked increase in sepsis, requiring continuous antibiotic prophylaxis.NoNoIXLT, Intermittent XLT; HSCT, hematopoietic stem cell transplantation; XLN, X-linked neutropenia.∗ Infections typical for neutropenia.† Patients with XLT with a score of 1 or 2 might progress to a score of 5. Incidence of autoimmunity and malignancies are less in XLT than in WAS.‡ Splenectomy results in increased platelet numbers and reduced bleeding but causes a marked increase in sepsis, requiring continuous antibiotic prophylaxis. Open table in a new tab IXLT, Intermittent XLT; HSCT, hematopoietic stem cell transplantation; XLN, X-linked neutropenia. The severity of the immune deficiency can vary from family to family, depending largely on the mutation and its effect on protein expression.11Imai K. Morio T. Zhu Y. Jin Y. Itoh S. Kajiwara M. et al.Clinical course of patients with WASP gene mutations.Blood. 2004; 103: 456-464Crossref PubMed Scopus (149) Google Scholar, 12Jin Y. Mazza C. Christie J.R. Giliani S. Fiorini M. Mella P. et al.Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation.Blood. 2004; 104: 4010-4019Crossref PubMed Scopus (119) Google Scholar Both T- and B-lymphocyte functions are affected. During infancy, the number of circulating lymphocytes might be normal or moderately decreased.13Ochs H.D. Slichter S.J. Harker L.A. Von Behrens W.E. Clark R.A. Wedgwood R.J. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets.Blood. 1980; 55: 243-252Crossref PubMed Google Scholar, 14Park J.Y. Kob M. Prodeus A.P. Rosen F.S. Shcherbina A. Remold-O'Donnell E. Early deficit of lymphocytes in Wiskott-Aldrich syndrome: possible role of WASP in human lymphocyte maturation.Clin Exp Immunol. 2004; 136: 104-110Crossref PubMed Scopus (38) Google Scholar By 6 years of age, lymphopenia caused by reduced T-lymphocyte numbers is a common finding in patients with classic WAS and might be due to accelerated cell death observed in patients with classic WAS, although not in those with XLT.15Rawlings S.L. Crooks G.M. Bockstoce D. Barsky L.W. Parkman R. Weinberg K.I. Spontaneous apoptosis in lymphocytes from patients with Wiskott-Aldrich syndrome: correlation of accelerated cell death and attenuated bcl-2 expression.Blood. 1999; 94: 3872-3882Crossref PubMed Google Scholar, 16Rengan R. Ochs H.D. Sweet L.I. Keil M.L. Gunning W.T. Lachant N.A. et al.Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells.Blood. 2000; 95: 1283-1292Crossref PubMed Google Scholar The number of B cells might be normal or moderately decreased.17Park J.Y. Shcherbina A. Rosen F.S. Prodeus A.P. Remold-O'Donnell E. Phenotypic perturbation of B cells in the Wiskott-Aldrich syndrome.Clin Exp Immunol. 2005; 139: 297-305Crossref PubMed Scopus (33) Google Scholar Serum IgG levels are generally within normal range, IgM levels are moderately decreased but can be normal or increased, and IgA and IgE levels are frequently increased. Antibody responses are adequate to some antigens and insufficient to others.3Sullivan K.E. Mullen C.A. Blaese R.M. Winkelstein J.A. A multiinstitutional survey of the Wiskott-Aldrich syndrome.J Pediatr. 1994; 125: 876-885Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar, 13Ochs H.D. Slichter S.J. Harker L.A. Von Behrens W.E. Clark R.A. Wedgwood R.J. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets.Blood. 1980; 55: 243-252Crossref PubMed Google Scholar, 18Cooper M.D. Chae H.P. Lowman J.T. Krivit W. Good R.A. Wiskott-Aldrich syndrome. An immunologic deficiency disease involving the afferent limb of immunity.Am J Med. 1968; 44: 499-513Abstract Full Text PDF PubMed Google Scholar Consistent findings are low isohemagglutinin titers, markedly decreased responses to polysaccharide antigens, and low antibody titers associated with defective class-switch recombination after immunization with the T cell–dependent neoantigen bacteriophage ΦX174.13Ochs H.D. Slichter S.J. Harker L.A. Von Behrens W.E. Clark R.A. Wedgwood R.J. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets.Blood. 1980; 55: 243-252Crossref PubMed Google Scholar In a multicenter retrospective review, antibody responses to a variety of protein antigens, including diphtheria and tetanus toxoid, and conjugated Haemophilus influenzae B vaccine were reported to be abnormal in the majority of patients with WAS; in contrast, antibody responses to live virus vaccines were mostly normal.3Sullivan K.E. Mullen C.A. Blaese R.M. Winkelstein J.A. A multiinstitutional survey of the Wiskott-Aldrich syndrome.J Pediatr. 1994; 125: 876-885Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar As expected, patients with XLT were found to have a more robust response to bacteriophage ΦX174, with amplification and isotope switching that is often comparable with that seen in healthy control subjects.19Ochs F.R.a.H. The Wiskott-Aldrich syndrome.in: Ochs H.D.S.C. Puck J. Primary immunodeficiency diseases, a molecular and genetic approach. Oxford University Press, New York1999: 292-305Google Scholar Abnormal T-cell function is suggested by diminished but not absent lymphocyte responses to mitogens,18Cooper M.D. Chae H.P. Lowman J.T. Krivit W. Good R.A. Wiskott-Aldrich syndrome. An immunologic deficiency disease involving the afferent limb of immunity.Am J Med. 1968; 44: 499-513Abstract Full Text PDF PubMed Google Scholar decreased proliferative responses to allogeneic cells,13Ochs H.D. Slichter S.J. Harker L.A. Von Behrens W.E. Clark R.A. Wedgwood R.J. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets.Blood. 1980; 55: 243-252Crossref PubMed Google Scholar and immobilized anti-CD3 mAb.20Molina I.J. Sancho J. Terhorst C. Rosen F.S. Remold-O'Donnell E. T cells of patients with the Wiskott-Aldrich syndrome have a restricted defect in proliferative responses.J Immunol. 1993; 151: 4383-4390PubMed Google Scholar Skin test results for delayed-type hypersensitivity were abnormal in 90% of patients studied.3Sullivan K.E. Mullen C.A. Blaese R.M. Winkelstein J.A. A multiinstitutional survey of the Wiskott-Aldrich syndrome.J Pediatr. 1994; 125: 876-885Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar An increased incidence of Pneumocystis carinii pneumonia also points to a significant T-cell defect in classic WAS. Recent studies suggest that B-cell function is equally affected. EBV-transformed B lymphoblasts derived from patients with WAS have reduced levels of F-actin and defective actin polymerization,21Facchetti F. Blanzuoli L. Vermi W. Notarangelo L.D. Giliani S. Fiorini M. et al.Defective actin polymerization in EBV-transformed B-cell lines from patients with the Wiskott-Aldrich syndrome.J Pathol. 1998; 185: 99-107Crossref PubMed Scopus (38) Google Scholar and B cells from patients lacking WASP have defective cell motility (as discussed later). WASP is also involved in innate immunity. In normal natural killer (NK) cells, WASP can easily be detected in the immunologic synapse, together with F-actin. In contrast, NK cells derived from patients with WAS lack WASP and show a markedly reduced accumulation of F-actin in the immunologic synapse. As a direct result, patients with WAS have defective cytolytic NK cell function.22Orange J.S. Ramesh N. Remold-O'Donnell E. Sasahara Y. Koopman L. Byrne M. et al.Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses.Proc Natl Acad Sci U S A. 2002; 99: 11351-11356Crossref PubMed Scopus (119) Google Scholar, 23Gismondi A. Cifaldi L. Mazza C. Giliani S. Parolini S. Morrone S. et al.Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect.Blood. 2004; 104: 436-443Crossref PubMed Scopus (69) Google Scholar This inhibition of NK cell–mediated cytotoxicity is associated with a reduced ability of these cells to form conjugates with susceptible target cells and to accumulate F-actin at the site of contact. The involvement of the actin cytoskeleton in cell migration and cell trafficking of myeloid cells, macrophages, dendritic cells (DCs), and Langerhans cells makes these cells particularly vulnerable to mutations of the WASP gene. Similarly, phagocytosis of particulate antigens and apoptotic cells is highly dependent on the formation of a specialized phagocytic actin cup, which is unsurprisingly compromised in cells deficient in WASP.24Lorenzi R. Brickell P.M. Katz D.R. Kinnon C. Thrasher A.J. Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis.Blood. 2000; 95: 2943-2946Crossref PubMed Google Scholar, 25Leverrier Y. Lorenzi R. Blundell M.P. Brickell P. Kinnon C. Ridley A.J. et al.Cutting edge: the Wiskott-Aldrich syndrome protein is required for efficient phagocytosis of apoptotic cells.J Immunol. 2001; 166: 4831-4834PubMed Google Scholar A striking deficiency observed in patients with WAS is the complete failure to assemble podosomes in monocytes, macrophages, and DCs, resulting in a severe defect of adhesion and motility.26Calle Y. Chou H.C. Thrasher A.J. Jones G.E. Wiskott-Aldrich syndrome protein and the cytoskeletal dynamics of dendritic cells.J Pathol. 2004; 204: 460-469Crossref PubMed Scopus (69) Google Scholar Transfection of full-length WASP cDNA into WASP-deficient macrophages restores chemotaxis in response to colony-stimulating factor 1.27Jones G.E. Zicha D. Dunn G.A. Blundell M. Thrasher A. Restoration of podosomes and chemotaxis in Wiskott-Aldrich syndrome macrophages following induced expression of WASp.Int J Biochem Cell Biol. 2002; 34: 806-815Crossref PubMed Scopus (66) Google Scholar Thrombocytopenia associated with small platelet volume is a consistent finding in patients with mutations of the WASP gene; exceptions are those with missense mutations within the Cdc42-binding site (Fig 1).7Devriendt K. Kim A.S. Mathijs G. Frints S.G. Schwartz M. Van Den Oord J.J. et al.Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.Nat Genet. 2001; 27: 313-317Crossref PubMed Scopus (207) Google Scholar, 28Burns S. Hardy S.J. Buddle J. Yong K.L. Jones G.E. Thrasher A.J. Maturation of DC is associated with changes in motile characteristics and adherence.Cell Motil Cytoskeleton. 2004; 57: 118-132Crossref PubMed Scopus (93) Google Scholar, 29Burns S. Cory G.O. Vainchenker W. Thrasher A.J. Mechanisms of WASp-mediated hematologic and immunologic disease.Blood. 2004; 104: 3454-3462Crossref PubMed Scopus (93) Google Scholar Platelet counts can vary from patient to patient within a family, from family to family, or within individual patients, with the numbers of platelets being as low as 5000/mm3 or as high as 50,000/mm3. Intermittent thrombocytopenia associated with unique amino acid substitutions in the WASP gene have been described in 2 families.6Notarangelo L.D. Mazza C. Giliani S. D'Aria C. Gandellini F. Ravelli C. et al.Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia.Blood. 2002; 99: 2268-2269Crossref PubMed Scopus (50) Google Scholar In most patients with WAS-XLT, the mean platelet volume is half (mean platelet volume = 3.8-5.0 fl) that of healthy control subjects.13Ochs H.D. Slichter S.J. Harker L.A. Von Behrens W.E. Clark R.A. Wedgwood R.J. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets.Blood. 1980; 55: 243-252Crossref PubMed Google Scholar After splenectomy, platelet counts and platelet volume increase but are still less than those of healthy control subjects.30Litzman J. Jones A. Hann I. Chapel H. Strobel S. Morgan G. Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome.Arch Dis Child. 1996; 75: 436-439Crossref PubMed Google Scholar, 31Haddad E. Cramer E. Riviere C. Rameau P. Louache F. Guichard J. et al.The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in proplatelet formation.Blood. 1999; 94: 509-518PubMed Google Scholar This partial recovery of platelet counts after splenectomy suggests that thrombocytopenia in patients with WAS-XLT is at least in part due to platelet destruction in the spleen or other reticular endothelial organs.32Grottum K.A. Hovig T. Holmsen H. Abrahamsen A.F. Jeremic M. Seip M. Wiskott-Aldrich syndrome: qualitative platelet defects and short platelet survival.Br J Haematol. 1969; 17: 373-388Crossref PubMed Google Scholar, 33Murphy S. Oski F.A. Naiman J.L. Lusch C.J. Goldberg S. Gardner F.H. Platelet size and kinetics in hereditary and acquired thrombocytopenia.N Engl J Med. 1972; 286: 499-504Crossref PubMed Google Scholar Increased expression of phosphatidylserine on the surface of circulating platelets from patients with WAS has been interpreted as an indication for increased phagocytosis and destruction of phosphatidylserine-positive platelets in the spleens of patients with WAS-XLT.34Shcherbina A. Rosen F.S. Remold-O'Donnell E. Pathological events in platelets of Wiskott-Aldrich syndrome patients.Br J Haematol. 1999; 106: 875-883Crossref PubMed Scopus (27) Google Scholar An alternative explanation is a decrease in platelet production. This possibility is suggested by the observations that autologous platelet survival in patients with WAS-XLT is only moderately reduced (5 ± 1.3 days [SD]).13Ochs H.D. Slichter S.J. Harker L.A. Von Behrens W.E. Clark R.A. Wedgwood R.J. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets.Blood. 1980; 55: 243-252Crossref PubMed Google Scholar A persistent finding has been a decrease in platelet turnover, which was found to be approximately 30% of the value observed in healthy subjects, indicating a significant platelet production defect. Because the marrow megakaryocyte mass is normal or increased in patients with WAS-XLT,13Ochs H.D. Slichter S.J. Harker L.A. Von Behrens W.E. Clark R.A. Wedgwood R.J. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets.Blood. 1980; 55: 243-252Crossref PubMed Google Scholar, 31Haddad E. Cramer E. Riviere C. Rameau P. Louache F. Guichard J. et al.The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in proplatelet formation.Blood. 1999; 94: 509-518PubMed Google Scholar it has been suggested that ineffective thrombocytopoiesis is at least in part responsible for the low platelet count. As a consequence of the platelet defect, the majority (84%) of patients with WAS have a history of bleeding, including epistaxis, oral bleeding, hematemisis and melena, and petechiae, purpura, or both. Life-threatening bleeding, including oral, gastrointestinal, and intracranial hemorrhage, occurred in 30% of patients with WAS, with intracranial hemorrhage observed in only 2%.3Sullivan K.E. Mullen C.A. Blaese R.M. Winkelstein J.A. A multiinstitutional survey of the Wiskott-Aldrich syndrome.J Pediatr. 1994; 125: 876-885Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar Eczema is one of the characteristic findings that originally differentiated WAS from ITP.1Wiskott A. Familiärer, angeborener Morbus Werlhofii?.Monatsschr Kinderheilkd. 1937; 68: 212-216Google Scholar The typical skin lesions resemble acute or chronic eczema in appearance and distribution. A history of eczema, mild or severe, transient or consistent, was reported by 81% of a large cohort of patients with WAS.3Sullivan K.E. Mullen C.A. Blaese R.M. Winkelstein J.A. A multiinstitutional survey of the Wiskott-Aldrich syndrome.J Pediatr. 1994; 125: 876-885Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar In its most severe form, eczema is resistant to therapy and persists into adulthood. Molluscum contagiosum, herpes simplex, or bacterial infections can develop in areas of the skin affected with eczema. Patients with XLT have either mild and transient eczema or none at all.11Imai K. Morio T. Zhu Y. Jin Y. Itoh S. Kajiwara M. et al.Clinical course of patients with WASP gene mutations.Blood. 2004; 103: 456-464Crossref PubMed Scopus (149) Google Scholar, 12Jin Y. Mazza C. Christie J.R. Giliani S. Fiorini M. Mella P. et al.Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation.Blood. 2004; 104: 4010-4019Crossref PubMed Scopus (119) Google Scholar It has been hypothesized that defective chemotaxis of DCs and Langerhans cells plays a role in the local generation of antigen-specific (most likely bacterial) T cells that are responsible for the development of eczema.35Thrasher A.J. Jones G.E. Kinnon C. Brickell P.M. Katz D.R. Is Wiskott-Aldrich syndrome a cell trafficking disorder?.Immunol Today. 1998; 19: 537-539Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar The eczema tends to be worse in families with a history of atopic diathesis, a finding suggesting that genes responsible for allergies might have a modifying affect. Autoimmune diseases are frequent in patients with WAS, being present in 40% of a large cohort of patients.3Sullivan K.E. Mullen C.A. Blaese R.M. Winkelstein J.A. A multiinstitutional survey of the Wiskott-Aldrich syndrome.J Pediatr. 1994; 125: 876-885Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar Most commonly reported is autoimmune hemolytic anemia, followed by vasculitis, renal disease, Henoch-Schönlein–like purpura, and inflammatory bowel disease. Other less frequent autoimmune diseases include neutropenia, dermatomyositis, recurrent angioedema, uveitis, and cerebral vasculitis. The incidence of autoimmune disease in patients with XLT is generally less frequent than in patients with classic WAS. However, a recent report form Japan suggests that autoimmune diseases are equally frequent in Japanese patients with a low clinical score, representing XLT, as in those with a high clinical score, representing WAS. IgA nephropathy, often causing chronic renal failure and requiring dialysis or renal transplantation, was a frequent complication in Japanese patients with the XLT phenotype.11Imai K. Morio T. Zhu Y. Jin Y. Itoh S. Kajiwara M. et al.Clinical course of patients with WASP gene mutations.Blood. 2004; 103: 456-464Crossref PubMed Scopus (149) Google Scholar A retrospective review of risk factors, clinical features, and outcomes of autoimmune complications in patients with mutations of WASP from a single center further underlines the importance of this problem.36Dupuis-Girod S. Medioni J. Haddad E. Quartier P. Cavazzana-Calvo M. Le Deist F. et al.Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients.Pediatrics. 2003; 111: e622-e627Crossref PubMed Google Scholar Of 55 patients with WAS, 40 had at least one autoimmune or inflammatory complication. Autoimmune hemolytic anemia was detected in 20 patients with onset before the age of 5 years; after 5 years, hemolytic anemia was present in 29%, neutropenia in 25%, vasculitis (including cerebral involvement) in 29%, inflammatory bowl disease in 9%, and renal disease in 3%. A high serum IgM concentration was a significant risk factor for the development of autoimmune disease or early death. Malignant tumors can occur during childhood but are more frequent in adolescents and young adults with the classic WAS phenotype. In the North American cohort studied by Sullivan et al,3Sullivan K.E. Mullen C.A. Blaese R.M. Winkelstein J.A. A multiinstitutional survey of the Wiskott-Aldrich syndrome.J Pediatr. 1994; 125: 876-885Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar malignancies were present in 13%, with an average age at onset of 9.5 years. Considering the increasing life expectancy, it is reasonable to assume that the incidence of malignancies will further increase as patients with WAS get older. The most frequent malignancy reported is B-cell lymphoma, often EBV positive, which suggests a direct relationship with a defective immune system. WAS-associated malignancies have a poor prognosis, as illustrated by the fact that only 1 of the 21 patients who had a malignancy was alive more than 2 years after establishing the diagnosis.3Sullivan K.E. Mullen C.A. Blaese R.M. Winkelstein J.A. A multiinstitutional survey of the Wiskott-Aldrich syndrome.J Pediatr. 1994; 125: 876-885Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar The incidence of malignancies in patients with the XLT phenotype is unknown but is less than in classic WAS. All hematopoietic stem cell (HSC)–derived lineages are functionally abnormal in patients with WAS, including lymphocytes, platelets, neutrophils, DCs, and Langerhans cells. This is not surprising because WASP is expressed in CD34+ stem cells and their progeny.37Wengler G. Gorlin J.B. Williamson J.M. Rosen F.S. Bing D.H. Nonrandom inactivation of the X chromosome in early lineage hematopoietic cells in carriers of Wiskott-Aldrich syndrome.Blood. 1995; 85: 2471-2477PubMed Google Scholar Although thrombocytopenia is a consistent finding in patients with WAS-XLT, the differentiation from ITP is often difficult because immunodeficiency and eczema might be absent at the initial evaluation. Laboratory evidence to establish the diagnosis, especially in patients with XLT, is therefore of prime necessity. The presence of small platelets is considered pathognomonic of WAS-XLT. Abnormal T- and B-lymphocyte functions are a consistent finding in classic WAS. The absence or reduced quantity of WASP in lymphocytes is the best confirmatory test short of mutation analysis.38Yamada M. Ohtsu M. Kobayashi I. Kawamura N. Kobayashi K. Ariga T. et al.Flow cytometric analysis of Wiskott-Aldrich syndrome (WAS) protein in lymphocytes from WAS patients and their familial carriers.Blood. 1999; 93: 756-757PubMed Google Scholar Lymphopenia is a consistent finding in classic WAS and might be present at an early age.14Park J.Y. Kob M. Prodeus A.P. Rosen F.S. Shcherbina A. Remold-O'Donnell E. Early deficit of lymphocytes in Wiskott-Aldrich syndrome: possible role of WASP in human lymphocyte maturation.Clin Exp Immunol. 2004; 136: 104-110Crossref PubMed Scopus (38) Google Scholar Iron deficiency anemia is common in infants and children with WAS-XLT becau
Referência(s)